A Novel ALK Secondary Mutation and EGFR Signaling Cause Resistance to ALK Kinase Inhibitors

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we rep...

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Published in:	Cancer research (Chicago, Ill.) Vol. 71; no. 18; pp. 6051 - 6060
Main Authors:	SASAKI, Takaaki, KOIVUNEN, Jussi, CAPELLETTI, Marzia, SHIMAMURA, Takeshi, ERCAN, Dalia, STUMPFOVA, Magda, YUN XIAO, WEREMOWICZ, Stanislawa, BUTANEY, Mohit, HEON, Stephanie, WILNER, Keith, CHRISTENSEN, James G, OGINO, Atsuko, ECK, Michel J, WONG, Kwok-Kin, LINDEMAN, Neal, GRAY, Nathanael S, RODIG, Scott J, JÄNNE, Pasi A, YANAGITA, Masahiko, NIKIFOROW, Sarah, ZHENG, Wei, LATHAN, Christopher, PAUL MARCOUX, J, JINYAN DU, OKUDA, Katsuhiro
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 15-09-2011
Subjects:	Antineoplastic agents Biological and medical sciences Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Cell Line, Tumor Cell survival Drug resistance Drug Resistance, Neoplasm Epidermal growth factor receptors Humans Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - genetics Lung Neoplasms - metabolism Medical sciences Models, Molecular Mutation Non-small cell lung carcinoma Oncogene Proteins, Fusion - biosynthesis Oncogene Proteins, Fusion - genetics Pharmacology. Drug treatments Protein Kinase Inhibitors - pharmacology Protein-tyrosine kinase Pyrazoles - pharmacology Pyridines - pharmacology Receptor Protein-Tyrosine Kinases - antagonists & inhibitors Receptor Protein-Tyrosine Kinases - genetics Receptor Protein-Tyrosine Kinases - metabolism Receptor, Epidermal Growth Factor - metabolism Signal Transduction Tumors Secondary Enzyme Transferases Epidermal growth factor receptor Resistance Signal transduction Kinase C-Onc gene Genetics Inhibitor Mutation Anaplastic lymphoma kinase Protooncogene
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Summary:	Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), including crizotinib, are effective treatments in preclinical models and in cancer patients with ALK-translocated cancers. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Here we report two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALK TKI (TAE684)-sensitive H3122 cell line. The crizotinib-resistant DFCI076 cell line harbored a unique L1152R ALK secondary mutation and was also resistant to the structurally unrelated ALK TKI TAE684. Although the DFCI076 cell line was still partially dependent on ALK for survival, it also contained concurrent coactivation of epidermal growth factor receptor (EGFR) signaling. In contrast, the TAE684-resistant (TR3) H3122 cell line did not contain an ALK secondary mutation but instead harbored coactivation of EGFR signaling. Dual inhibition of both ALK and EGFR was the most effective therapeutic strategy for the DFCI076 and H3122 TR3 cell lines. We further identified a subset (3/50; 6%) of treatment naive NSCLC patients with ALK rearrangements that also had concurrent EGFR activating mutations. Our studies identify resistance mechanisms to ALK TKIs mediated by both ALK and by a bypass signaling pathway mediated by EGFR. These mechanisms can occur independently, or in the same cancer, suggesting that the combination of both ALK and EGFR inhibitors may represent an effective therapy for these subsets of NSCLC patients.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-11-1340